When scientists first reported they had found a way to make an ordinary skin cell behave like a stem cell from a human embryo, everyone from researchers to religious groups fell hard for the idea.
The creation of an embryonic-like stem cell without an embryo – a regular old skin cell, the kind people slough off daily, tricked back into a primitive state so that it could be grown into all the tissue types that make up the body? The attraction was – and remains – irresistible.
Reprogrammed cells negate any need to destroy human embryos to harvest stem cells, and silence the field's moral controversies. They could, theoretically, be grown from a patient's own cells to repair damaged organs, without fears of immune system rejection.
Four years later, the desire to skirt the ethical divide, while delivering tailor-made treatments for everything from diabetes to neurological disorders, is an epic challenge.
A gathering of the world's stem-cell scientists in Toronto this past week made it clear that working with these embryonic mimics has turned out to be trickier than expected. The promise of reprogrammed stem cells remains elusive.
"The [question]is whether they are equivalent to embryonic stem cells, and that is still up in the air," said Andras Nagy, a senior investigator at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, who is growing and working with both cell types. "We are hoping the [reprogrammed]cells are going to be the winner in this game, but we cannot say.
"There is a lot still to understand."
Studies have piled up casting doubt on the medical value of the reprogrammed cells – known as induced Pluripotent Stem Cells, or iPS cells for short. A number of reports say they carry an unexpectedly high number of genetic changes that could make them unstable, or cause cancer. Other research has found the reprogrammed cells retain the memory of their former lives, which could make them unpredictable over the long term. And surprisingly, one recent mouse experiment suggests that patients might still reject transplanted tissue grown from these cells – even when they came from their own bodies.
Experts agree the cells are more readily useful as models to study a specific patient's disease, and to design and test new drugs. The challenge is that no two reprogrammed cells seem to be alike, and researchers have to be sure what they see in the dish reflects the patient's disease and not errors caused by reprogramming.
Gordon Keller, director of the McEwen Centre for Regenerative Medicine, says the challenges of working with iPS cells were to be expected. Researchers are taking a mature, regular human skin cell, turning back its molecular clock to a time before birth, and with a fate yet to be defined. Then, once they get it there, they have to fool that cell once again, and make it to commit to a new life as a cell of the liver, say, or the heart.
"We're expecting to take [it]back in time in two or three weeks … marching through development from stage one … and then we hope we can accelerate that development," said Dr. Keller. "You can't expect it to be pristine."
And as with stem cells taken from embryos, the cells reprogrammed to act embryonic tend to produce cells and tissues more suitable for a fetus than an adult, said Mick Bhatia, scientific director of the Stem Cell and Cancer Research Institute at McMaster University in Hamilton.
Blood cells made from a stem cell, for instance, often have a 70 per cent higher affinity for oxygen because they are intended for the fetus, which has to "suck its oxygen from the mother during development in utero," said Dr. Bhatia. The cardiac cells of a fetus also have a much faster heart rate than those of an adult.
The McEwen centre ships its batches of heart cells to about 10 different international groups of cardiac specialists weekly to find ways to make the cells mature more quickly. One team is stretching them by mechanical means, said Dr. Keller, another is testing electrocution to accelerate their development.
"This is a huge area of research," said Dr. Nagy, who is also a McEwen scientist and the Canada research chair in stem cells and regenerative medicine. "I'm quite positive there will be a solution."
But even if there is one, the big question is whether all the reprogramming and manipulation will trigger too many genetic mutations to make the cell useful.
Researchers have found the reprogrammed cells contain actual changes to DNA code, and changes that affect "how the DNA works and which genes are expressed," said Dr. Nagy.
It may be, he said, that scientists will have to figure out which adult cells are the least likely to suffer genetic damage when they are reprogrammed. So far, embryonic-like stem cells have been grown from various tissues, including skin, blood and even a single follicle of hair. And they are powerful. Dr. Nagy said mouse cells reprogrammed can grow into a completely new animal – "a clear testament that they can do anything."
As it stands, Dr. Bhatia said, working with the reprogrammed cells is testing the "limits of technology and expertise." Those limits, he added, suggest that researchers may be working toward "a very boutique industry" with treatments that cost hundreds of thousands of dollars and are unlikely to be underwritten by provincial health plans.
"I'm not trying to be a kill-joy here," he said, "just a sober voice. All this will be figured out, but it will take time and an incredible amount of money."
Dr. Nagy hopes that as researchers "learn reprogramming so well" they will be able to "bypass the embryonic stage completely," take adult cells and "drive them directly to their destinations" as new heart cells, for example.
Work is already under way in that direction. Last December, Dr. Bhatia and his team reported that they had managed to turn a human skin cell directly into a blood cell. Others have reported remaking skin cells into liver cells and neurons.
For the moment, Dr. Nagy said, "The smart thing is to have both [embryonic and reprogrammed]systems running in parallel. In my lab, the embryonic stem cells are the gold standard, and we see if the iPS are the same and how they measure up."
As Dr. Nagy noted: "The pace of research is enormously rapid. I haven't seen a field in life science ever moving as fast as this one."
Problems with stem cells
The cells created by reprogramming a patient's own cells function more like the cells found in a fetus than those found in adult. That creates problems when trying to use them to treat conditions in the patient:
FETUS – the blood cell produces proteins with an estimated 70 per cent higher ability to bind to oxygen because it must be drawn from the mother's blood through the placenta and umbilical cord
ADULT – the cell produces proteins with less affinity to bind to oxygen because it can be breathed directly into the lungs
FETUS – cardiac cells run a rate of roughly 150 beats per minute during pregnancy, to pump enough oxygenated blood through the tiny body without functioning lungs taking in air to breathe on their own
ADULT – cardiac cells have a resting heart rate about twice as slow as those of a fetus as the circulatory and respiratory systems rely on oxygen drawn directly from the air
FETUS – liver cells are immature since the fetus relies on mother's nutrients for support and the organ does not work as a digestive filter. Nor does it produce all the enzymes necessary for digestion or drug metabolism.
ADULT – liver cells play a major role in metabolism and other biological systems, including detoxification, the making of hormones and the production of enzymes needed for digestion and to process drugs